Pyrimidine-annulated pyrrolobenzodiazepines. a new ring system related to aspergillus alkaloids

Article abstract of DOI:10.1002/ejoc.200400738

Pyrrolo[2,1-c][1,4]benzodiazepine-5,11-dione was converted into the corresponding C-11-monothiolactam and subsequently treated with amines to give cyclic amidines, which racemize due to the formation of tautomers (NMR, X-ray analysis) under basic conditions. We treated these amidines with bis(trichlorophenyl) malonate esters. Formation of neutral tautomers of the 1,3,8-triones of the new 4,7a,12b-triaza dibenzo[e,g]azulene ring system gave a twisted molecule with both helical and chiral structure elements (NMR, X-ray analysis), which caused a splitting of the NMR signals into two sets. Results of two X-ray single crystal analyses are presented, together with an ab initio calculation. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005.

Full text of DOI:10.1002/ejoc.200400738

FULL PAPER
Pyrimidine-Annulated Pyrrolobenzodiazepines. A New Ring System Related to
Aspergillus Alkaloids
Andreas Schmidt,*[a] Abbas Gholipour Shilabin,[a] Jan Christoph Namyslo,[a]
Martin Nieger,[b] and Sascha Hemmen[c]
Keywords: Betaines / Nitrogen heterocycles / Tautomerism / Conformation analysis
Pyrrolo[2,1-c][1,4]benzodiazepine-5,11-dione was converted
into the corresponding C-11-monothiolactam and sub-
sequently treated with amines to give cyclic amidines, which
racemize due to the formation of tautomers (NMR, X-ray
analysis) under basic conditions. We treated these amidines
with bis(trichlorophenyl) malonate esters. Formation of neu-
tral tautomers of the 1,3,8-triones of the new 4,7a,12b-triaza-
dibenzo[e,g]azulene ring system gave a twisted molecule
with both helical and chiral structure elements (NMR, X-ray
analysis), which caused a splitting of the NMR signals into
two sets. Results of two X-ray single crystal analyses are pre-
sented, together with an ab initio calculation.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
on nucleophilic attack of the exocyclic N2 of a guanine at
the electrophilic C(11)-position after sequence-selective in-
sertion in the minor groove (Scheme 1).[19,20,21,22,23]
Introduction
Pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) form a class
of biologically active compounds. Special interest is cur-
rently focused on new derivatives[1,2,3] that can recognize
and bind to specific sequences of DNA[4,5,6,7] and cause a
wide variety of potential biological responses. In this con-
text, PDBs are one of the most promising types of lead
compounds.[8] Some derivatives possess cancerostatic and
antiinfective properties[9,10] and can be used as affinity-
cleavage reagents in molecular biology.[11] The PBD ring
system is also found in natural antitumor antibiotics such
as anthramycin,[12,13,14] and many others.[15,16,17,18] All the
naturally occurring compounds possess the S configuration
at the α-carbon atom of the pyrrolidine ring [i.e., C(11a)],
which provides them with a right-handed twist and causes
isohelicity with the minor groove of the double-stranded
B form of DNA. This configuration has been identified as
important to the pharmacophore of these compounds. The
biological activity of anthramycin, tomaymycin, chicamy-
cin, neothramycin, and other PBDs from Streptomyces spe-
cies is due inter alia to their ability to form aminal bonds
Scheme 1. Attack of guanine on pyrrolobenzodiazepines after in-
sertion into the minor groove of DNA.
In continuation of our interest in alkaloids,[24,25,26,27] nu-
cleobase betaines,[28,29] and ionic heteroaromatics,[30,31,32]
we became interested in this class of compounds because
some alkaloids, circumdatin A–G, had been isolated from
the fungus Aspergillus ochraceus and proposed as suitable
chemotaxonomic markers for this species.[33] Total synthe-
ses of circumdatin C and F,[34] and a building block ap-
proach to a diverse multi-arrayed library of the circumda-
tin family by means of aza-Wittig reactions[35] were pub-
lished recently, demonstrating the interest in derivatives of
this ring system. We focused our attention on compounds
related to the proposed structures 1 and 2 for circumdatin A
and B (Scheme 2), which are heterocyclic mesomeric beta-
ines, in order to study stereochemical and spectroscopic ef-
fects of possible tautomerism, in particular in view of the
biological relevance of the twisted conformation of the pyr-
rolobenzodiazepine ring system. Here we report our results
concerning the syntheses and surprising spectroscopic prop-
erties of structures related to these natural products, diox-
[a] Clausthal University of Technology, Institute of Organic Chem-
istry,
Leibnizstrasse 6, 38678 Clausthal-Zellerfeld, Germany
Fax: +49-5323-723861
E-mail: schmidt@ioc.tu-clausthal.de
[b] Rheinische Friedrich-Wilhelms-Universität Bonn, Institute of
Inorganic Chemistry,
Gerhard-Domagk-Strasse 1, 53121 Bonn, Germany
Fax: +49-228-735327
E-mail: m.nieger@uni-bonn.de
[c] Clausthal University of Technology, Institute of Theoretical
Physics, Dept. of Applied Theoretical Physics,
Leibnizstrasse 10, 38678 Clausthal-Zellerfeld, Germany
Fax: +49-5323-723116
E-mail: sascha.hemmen@tu-clausthal.de
Eur. J. Org. Chem. 2005, 1781–1789
DOI: 10.1002/ejoc.200400738
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A. Schmidt, A. Gholipour Shilabin, Jan C. Namyslo, M. Nieger, S. Hemmen
FULL PAPER
opyrimidine-annulated pyrrolobenzodiazepines, the first ortho-protons of the aniline moiety and C(11a)-H of 9, and
representatives of a new ring system.
couplings of the more shielded NH-group with C(9)-H and
C(11a)-H, respectively. Thus, the ratios of 8A/8B, 9A/9B,
and 10A/10B at 20 °C in [D6]DMSO were determined to be
10:11, 10:6, and 10:12, respectively, with these ratios chang-
ing with temperature. As an example, the 9A/9B ratio
changes to 10:11 at 100 °C in [D6]DMSO. The tautomeric
forms 8C and 9C, the bases of racemization of the pyrroli-
dine moiety, were not detected spectroscopically, and a con-
trol experiment with the piperidino derivative 11 confirmed
1
these observations. No traces of 11B were found in the H
NMR spectra in [D6]DMSO; only one set of signals was
observable regardless of the solvent used.
Scheme 2. Proposed structures for circumdatin A (1) and (B) 2.
In the solid state, compound 9 exists as the exocyclic im-
ine 9B in the Z configuration, as evidenced by a single-
crystal X-ray analysis (Figure 1).[40] The phenylimino group
is strongly twisted out of the plane defined by the phenyl
ring of the benzodiazepine moiety. The bond length of the
C=N bond [crystallographic numbering: C2–N2] was deter-
mined to be 128.03(13) pm, whereas the N(10)–C(11) dis-
tance [N1–C2] is 138.07(13) pm. The bond length between
C(11) and C(11a) [C2–C2A] is 151.61(13) pm.
Methylation of racemic 9 with sodium hydride and
methyl iodide gave only product 12 (Scheme 5), as evi-
denced by couplings of the methyl group to C(9a) and
C(11) in HMBC NMR experiments.
Results and Discussion
We started our investigation from the pyrrolo[2,1-c][1,4]
benzodiazepine natural product
4
(from Isatis in-
digotica[36]), which is readily available by heating isatoic an-
hydride 3 at reflux with (S)-proline in DMF by literature
procedures.[37,38] Its methylated derivative 5 was obtained
analogously by starting from (S)-α-methylproline. Thion-
ation in THF at room temperature with 2,4-bis(4-meth-
oxyphenyl)-1,3-dithia-2,4-diphosphetane
2,4-disulfide
(Lawesson’s reagent)[39] resulted in the formation of the
monothiolactams 6 and 7 in good yields (Scheme 3).
We then treated the amidines 8–10 with bis(2,4,6-trichlo-
rophenyl) 2-phenylmalonates (Scheme 6) in order to obtain
the target pyrimidine-annulated pyrrolobenzodiazepines.
Heating of the starting materials in a Zincke apparatus gave
2,4,6-trichlorophenol as expected, and this was distilled off
in vacuo. On recrystallization of the residues obtained from
8 and 9 pale yellow solids were obtained in good yields,
whereas no isolable compounds were obtained when start-
ing from the methylated species 10. All NMR spectra taken
in CDCl3 are in agreement with tautomers 13B and 14B,
resulting from elimination of the α-hydrogen atoms of the
pyrrolidine ring. The NMR spectra in CDCl3 clearly indi-
cate the existence of only three CH2 groups and one CH
group, joined to the phenyl group. These results corroborate
the formation of a 3H-2,4-dioxopyrimidine ring and a sp2-
hybridized C-11a in tautomers 13B and 14B, instead of the
cross-conjugated mesomeric betaines 13A and 14A in
CDCl3 solution. These findings explain the failure of the
Scheme 3.
The monothiolactams 6 and 7 reacted with amines such reaction of 10 to give 15, which would be compelled to
as aniline, methylamine, and piperidine in the presence of adopt a clearly unstable betainic structure 15A.
mercury(ii) chloride to afford the cyclic amidines 8–11 in
A striking feature of 13 and 14, however, is a doubling
1
high yields (Scheme 4). We observed that the neat reaction of the H NMR and 13C NMR resonance frequencies in
of 6 and the amines (except for methylamine, which was [D6]DMSO, C6D6, [D7]DMF, and MeOD (Figure 2).
used as a solution in THF) gave better yields than reactions Whereas traces of acids and bases do not cause any changes
conducted in THF. We obtained 8 and 10 as optically active in the spectra taken in CDCl3, splitting of the signals is
compounds, whereas 9 racemized under these conditions. observable on addition of [D6]DMSO to this solution, the
1
In the H NMR spectra of 8–10 in CDCl3 at 20 °C only chemical shift difference depending on the relative concen-
one set of signals is present. In [D6]DMSO at 20 °C, how- tration of these two solvents.
ever, two distinct tautomeric forms of 8–10 are detectable.
As evidenced by HSQC, HMBC, and NOESY experi-
Unambiguous peak assignments through a combination of ments and by 13C NMR, either form of 14 possesses the
HSQC and HMBC NMR experiments established the C(= O)–CHPh–C(= O) partial structure, so that the forma-
coupling of the more deshielded NH group with the two tion of tautomers such as the mesomeric betaine 14A and
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A New Ring System Related to Aspergillus Alkaloids
FULL PAPER
Scheme 4. Tautomeric forms of 11-amino-substituted pyrrolobenzodiazepines.
Figure 1. Molecular structure of 9 according to a single-crystal X-
ray analysis.
Scheme 5. Methylation of 9 occurs at N(10).
enols such as 14C in the above solvents were ruled out.
NOESY experiments, however, detected closely spaced pro-
tons of the pyrrolidine and of the phenyl ring at C-2 (15-
Scheme 6. Treatment with trichlorophenyl malonates results in the
formation of tautomers 13B/14B instead of cross-conjugated meso-
H↔5-H, 15-H↔6-H, 15-H↔7-H, 16-H↔5-H, 16-H↔6-H) meric betaines 13A/14A or enols such as 13C/14C.
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A. Schmidt, A. Gholipour Shilabin, Jan C. Namyslo, M. Nieger, S. Hemmen
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Figure 2. NMR spectra of 14 in various solvents.
in one of the two conformers observable in the spectra. This
In order to confirm these assumptions, we performed ab
finding provides evidence for a conformation of 14 in which initio calculations on boat and chair conformations of the
these partial structures are situated in close proximity, dioxopyrimidine ring of 14 with equatorial (II, III) and ax-
which causes the more shielded resonance frequencies. A ial (I, IV) substituents at C-2, respectively (Scheme 7). All
boat conformation of the dioxopyrimidine moiety with an calculations were carried out with the projector-augmented
axial phenyl ring at C-2 could explain the proximity of these wave method[41] as implemented in the PAW program.[41–45]
partial structures, and this assumption was supported by The calculations show that the boat conformation with ax-
the chemical shift difference of 2-H, which is consistent ial phenyl ring (I) indeed has the lowest total energy. The
with axial and equatorial positions. Interconversion of the difference with the boat conformation with equatorial
ring system in CDCl3 is obviously fast. As the CDCl3 solu- phenyl ring (III) is ΔE = 8.9 kJ mol–1. Both axial (IV) and
tions solidified to glassy materials on cooling, however, we equatorial phenyl rings (II) in chair conformations have
were prevented from taking NMR spectra at low tempera- higher energies, of ΔE
= =
78.0 kJ mol–1 and ΔE
tures. We were able to assign the resonance frequencies to 58.2 kJ mol–1, respectively. In addition, the calculations
the two forms unambiguously from the spectra, and our show twisted conformations of the pyrrolobenzodiazepine
results are presented in Table 1.
partial structure.
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A New Ring System Related to Aspergillus Alkaloids
Table 1. Chemical shifts of 14 in CDCl3 and [D6]DMSO.
FULL PAPER
Atom no.
13C NMR (CDCl3)
1H NMR (CDCl3)
13C NMR ([D6]DMSO)
1H NMR ([D6]DMSO)
1
2
3
166.7
62.3
166.7
128.6
119.3
29.3
–
166.2/166.7
59.3/62.0
166.5/166.8
128.9
118.7/118.1
29.3/29.8
–
4.94 (s)
–
–
–
1.61–1.65 (m)
1.73–1.80 (m)
0.88–1.00 (m)
1.54–1.60 (m)
3.41–3.47 (m)
3.66–3.73 (m)
–
4.79 (s)/5.54 (s)
–
–
4a[a]
4b
5
–
1.63–1.68 (m)/1.87–2.01 (m)
1.79–1.84 (m)/1.87–2.01 (m)
0.83–0.94 (m)/1.77–1.85 (m)
1.58–1.62 (m)/1.77–1.85 (m)
3.29–3.35 (m)/3.82–3.86 (m)
3.55–3.62 (m)/3.82–3.86 (m)
–
6
7
19.8
49.5
19.9/20.3
49.8/50.4
8
8a
9
165.2
139.5
132.9
134.1
128.4
126.2
139.5
133.2
126.3
129.5
132.1
139.0
124.2
129.7
126.8
164.8/165.3
139.9
132.5
134.2/134.4
128.7
127.3/127.4
140.4
133.4
126.5
129.9
128.9
–
–
8.08 (dd)
7.70 (ddd)
7.48 (ddd)
7.53 (dd)
–
7.92 (dd)/7.93–7.96 (m)
7.76–7.77 (m)/7.72–7.74 (m)
7.51–7.55 (m)/7.48–7.52 (m)
7.75 (d)/7.71–7.72 (m)
–
10
11
12
12a
13[a]
14
15
16
17
18
19
20
–
–
7.40–7.44 (m)
7.37–7.40 (m)
7.35–7.37 (m)
–
7.18–7.20 (m)
7.29–7.33 (m)
7.15–7.18 (m)
7.45–7.48 (m)
7.37–7.39 (m)
7.41–7.42 (m)
–
7.18–7.21 (m)
7.33–7.35 (m)
7.22–7.23 (m)
139.5
124.9/125.1
130.1
127.1
[a]: Peak assignments exchangeable.
Scheme 7. Boat-chair isomerizations I/II and III/IV (above), and racemizations via anionic species V (below) of the dioxopyridimidine
moiety of 14.
These results are in qualitative agreement with an X-ray and the phenyl ring at C3 in axial position (Figure 4). The
single crystal analysis of 14, which shows tautomer 14B in phenyl ring is twisted by –30.16(12)° [C4–C3–C31–C32,
the solid state (Figure 3): The 6:7:5 pyrrolobenzodiazepine calcd. –34.2°].
ring system adopts a twisted conformation. The C6–C7
The ab initio calculation gave a bond length of 135.3 pm
bond length is 132.71(16) pm (calcd. 135.2 pm), which cor- between C-4a and C-4b [crystallographic numbering: C6–
responds to a C(sp2) = C(sp2) double bond. This C=C bond C7] in conformer III (Scheme 7) in which the phenyl ring is
is twisted due to the helicity of the 6:7:5 ring system, so in an equatorial position in the boat conformation of the
that the dihedral angles N1–C6–C7–N11 and N5–C6–C7– dioxopyrimidine moiety. Again, this double bond is twisted
C8 are 4.77(18)° and 6.37(19)°, respectively [calcd. 4.9° and by –3.5° (C6–N1–C2–C3).
4.7°, respectively]. In the elemental cell, the 3H-2,4-dioxo-
Conversion of the configuration at C-2 of 14 must pro-
pyrimidine ring adopts a boat-like conformation with C6 ceed via an anionic species V as represented in Scheme 7.
and C3 above the plane formed by N1, N5, C4, and C2, On isomerization, the phenyl ring changes from an axial
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A. Schmidt, A. Gholipour Shilabin, Jan C. Namyslo, M. Nieger, S. Hemmen
FULL PAPER
Scheme 8. Deprotonation and methylation.
In summary, we present the first representatives of a new
ring system, 4,5,6,7-tetrahydro-4,7a,12b-triaza-dibenzo[e,g]
azulene and its precursors, which are related to biologically
interesting natural products and display a priori unexpected
spectroscopic features.
Figure 3. Results of an X-ray analysis of 14. The drawing shows
the helicity of the benzopyrrolodiazepine moiety of 14.
Experimental Section
1
General Remarks: The H and 13C NMR spectra were recorded on
Bruker ARX 400 and DPX 200 spectrometers and were taken in
[D6]DMSO and CDCl3 at 200 and 400 MHz. The chemical shifts
are reported in ppm relative to internal tetramethylsilane (δ =
0.00 ppm). Multiplicities are described by the following abbrevi-
ations: s = singlet, d = doublet, t = triplet, m = multiplet, br =
broad. FT-IR spectra were obtained on a Bruker Vektor 22 instru-
ment in the 400 to 4000 cm–1 range (2.5% pellets in KBr). The GC-
MS spectra (EI) were recorded variously on a GC Hewlett Pack-
ard 5980, Serie II/MS Hewlett Packard 5989 B, or on a Varian
GC3900 with SAT2100T. The ESI mass spectra were measured
with an Agilent LCMSD Series HP1100 with APIES. Samples were
sprayed from methanol at 0 V fragmentor voltage unless otherwise
noted. All reactions were monitored by analytical thin layer
chromatography on precoated plates (silica gel 60 F254) and spots
were detected either by UV absorption or by treatment with iodine.
All commercially available chemicals were purchased from Fluka,
Aldrich, and Lancaster Chemical Co. and were used as received
without further purification.
1,2,5,10,11,11a-Hexahydro-11a-methyl-3H-pyrrolo[2,1-c][1,4]benzo-
diazepine-5,11-dione (5): Isatoic anhydride (1.84 g, 11.3 mmol) and
(S)-α-methylproline (1.47 g, 11.3 mmol) were dissolved in DMF
(10 mL) and were then heated under reflux for 3 h. After cooling,
the solvent was removed under reduced pressure to yield an oily
residue. Purification by flash column chromatography on silica gel
(petroleum ether/ethyl acetate, 5:1) afforded 5 as a colorless solid
Figure 4. X-ray analysis of 14. In the single crystal, the dioxopyrim-
idine fragment of 14 adopts a boat-like conformation with the (2.0 g, 8.7 mmol, 77%). m.p. 203–204 °C. [α]2D0 = +385.9 (c = 1.0 in
CHCl3). 1H NMR (200 MHz, CDCl3): δ = 1.23 (s, 3 H, CH3), 1.74–
phenyl ring at C3 in axial position.
1.96 (m, 3 H, 1-H, 2-H), 3.06–3.22 (m, 1 H, 1-H), 3.64–3.78 (m, 1
H, 3-H), 3.92–4.02 (m, 1 H, 3-H), 6.99 (dd, J8,9 = 8.02, J7,9
=
0.95 Hz, 1 H, 9-H), 7.20–7.28 (m, 1 H, 8-H), 7.43–7.51 (m, 1 H, 7-
H), 8.02 (dd, J6,7 = 7.89, J6,8 = 1.58 Hz, 1 H, 6-H), 8.66 (br. s, 1
H, NH) ppm. 13C NMR (50 MHz, CDCl3): δ = 21.7 (C-2), 22.1
(CH3), 38.7 (C-1), 49.8 (C-3), 66.28 (C-11a), 119.7/124.6/126.0/
131.4/132.6/135.3 (Ph), 165.1 (CO), 173.3 (CO) ppm. IR (KBr,
into an equatorial position, which must be accompanied by
a considerable change of the NMR signals. In order to con-
firm these assumptions, we deprotonated 14 with NaH in
dimethoxyethane and indeed obtained the anionic molecule
16, which is a stable yellow solid (Scheme 8). The anion
cm–1): ν = 3227 (N–H), 3069, 2997, 1677 (C=O), 1630 (C=O), 1483,
˜
1
1435, 1404, 1361, 1256, 1180 cm–1. MS (EI, 70 eV): m/z (%) = 230
displays a single set of signals in the H NMR spectra, re-
gardless of the solvent used. In electrospray ionization mass (99) [M]+, 187 (100), 119 (16), 84 (54), 63 (17). C13H14N2O2
(230.26): calcd. C 67.81, H 6.13, N 12.17; found C 67.49, H 6.07,
N 12.06.
spectrometry in methanol in the negative ion detection
mode, the molecular peaks appear at m/z = 434.0 u as base
peak. Methylation of the salt 16 with methyl iodide gave 17
in good yield.
1,2,5,10,11,11a-Hexahydro-11a-methyl-11-thioxo-3H-pyrrolo[2,1-c]-
[1,4]benzodiazepin-5-one (7): A mixture of dilactam 5 (2.30 g,
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A New Ring System Related to Aspergillus Alkaloids
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10.0 mmol) and Lawesson’s reagent (2.02 g, 5.0 mmol) in THF
(40 mL) was stirred overnight at room temperature. Evaporation of
the solvent in vacuo gave a solid residue, which was purified by
flash column chromatography on silica gel (dichloromethane/ace-
9-H), 6.91 (d, J = 7.5 Hz, 2 H, Ph), 7.10–7.17 (m, 2 H, Ph), 7.32–
7.41 (m, 3 H, Ph), 7.95 (dd, J6,7 = 7.9, J6,8 = 1.5 Hz, 1 H, 6-H) ppm.
1H NMR (400 MHz, [D6]DMSO) of 9A: δ = 1.90–2.22 (m, 3 H, 1-
H, 2-H), 2.80–2.84 (m, 1 H, 1-H), 3.50–3.57 (m, 1 H, 3-H), 3.63–
tone, 100:1) to give monothiolactam 7 as a yellow solid (1.77 g, 3.72 (m, 1 H, 3-H), 4.31 (d, J1,11a = 5.6 Hz, 1 H, 11a-H), 6.75 (d,
7.20 mmol, 72%). m.p. 258–260 °C. [α]2D0 = +113.1 (c = 0.2 in
J = 7.3 Hz, 2 H, Ph), 7.01–7.13 (m, 3 H, Ph), 7.29–7.34 (m, 2 H,
CHCl3). 1H NMR (200 MHz, [D6]DMSO): δ = 1.14 (s, 3 H, CH3), Ph), 7.36–7.40 (m, 1 H, 7-H), 7.73 (dd, J6,7 = 8.0, J6,8 = 1.5 Hz, 1
1
1.71–1.86 (m, 2 H, 2-H), 1.90–2.09 (m, 1 H, 1-H), 3.40–3.61 (m, 2 H, 6-H), 7.84 (d, J = 7.6 Hz, 2 H, Ph), 8.36 (s, 1 H, NH) ppm. H
H, 1-H, 3-H), 3.71–3.81 (m, 1 H, 3-H), 7.29–7.37 (m, 2 H, 8-H, 9-
NMR (400 MHz, [D6]DMSO) of 9B: δ = 1.90–2.22 (m, 3 H, 1-H,
H), 7.53–7.62 (m, 1 H, 7-H), 7.83 (dd, J6,7 = 8.08, J6,8 = 1.64 Hz,
2-H), 2.80–2.84 (m, 1 H, 1-H), 3.33–3.44 (m, 1 H, 3-H), 3.63–3.72
1 H, 6-H), 12.47 (br. s, 1 H, NH) ppm. 13C NMR (50 MHz, [D6]- (m, 1 H, 3-H), 4.07 (d, J1,11a = 7.2 Hz, 1 H, 11a-H), 7.01–7.13 (m,
DMSO): δ = 20.6 (C-2), 22.2 (CH3), 42.4 (C-1), 49.4 (C-3), 66.3 (C-
3 H, Ph), 7.29–7.34 (m, 2 H, Ph), 7.40–7.41 (m, 1 H, 7-H), 7.78
(dd, J6,7 = 7.9, J6,8 = 1.7 Hz, 1 H, 6-H), 7.84 (d, J = 7.6 Hz, 2 H,
Ph), 8.42 (s, 1 H, NH) ppm. 13C NMR (100 MHz, CDCl3): δ =
23.8 (C-2), 27.2 (C-1), 47.8 (C-3), 57.1 (C-11a), 120.7/121.6/124.2/
11a), 120.7/125.4/126.4/130.4/132.4/136.6 (Ph), 163.6 (CO), 205.0
(CS) ppm. IR (KBr, cm–1): ν = 3178 (N–H), 2968, 1605 (C=O),
˜
1582, 1519, 1479, 1419, 1352, 1270, 1146, 1108, 1076 cm–1. MS (EI,
70 eV): m/z (%) = 247 (24) [M + 1]+, 162 (8), 84 (100). C13H14N2OS 124.3 (Ph), 126.9 (C-11), 130.4/131.6/132.6/137.1/148.1/154.0 (Ph),
(246.33): calcd. C 63.39, H 5.73, N 11.37; found C 63.16, H 5.62,
N 11.29.
166.4 (CO) ppm. 13C NMR (100 MHz, [D6]DMSO) of 9A: δ = 23.8
(C-2), 27.4 (C-1), 47.6 (C-3), 57.3 (C-11a), 122.1/122.7/123.5/123.7
(Ph), 127.4 (C-11), 130.2/130.9/132.5/138.7/149.2/153.7 (Ph), 165.8
(CO) ppm. 13C NMR (100 MHz, [D6]DMSO) of 9B: δ = 24.50 (C-
2), 26.8 (C-1), 47.1 (C-3), 55.9 (C-11a), 122.3/122.9/123.4/124.1
(Ph), 127.3 (C-11), 129.1, 130.4, 132.1, 140.5, 147.6, 155.8 (Ph),
1,2,3,11a-Tetrahydro-11-(methylamino)-5H-pyrrolo[2,1-c][1,4]benzo-
diazepin-5-one (8): A solution of monomethylamine in THF (2 m,
20 mL, 40 mmol) was added at room temperature to a suspension
of monothiolactam 6 (2.32 g, 10 mmol) and HgCl2 (3.26 g,
12 mmol) in THF (100 mL) and the mixture was stirred for 30 min
at the same temperature. The mixture was then heated at reflux for
15 min. After cooling, the mixture was filtered off through a plug
of Celite and dried over MgSO4. Evaporation of the solvent in
vacuo gave a white, solid residue, which was recrystallized from
acetonitrile to afford 8 as colorless crystals (1.90 g, 8.30 mmol,
83%). m.p. 204–206 °C. [α]2D0 = +1190.4 (c = 1.0 in CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 1.99–2.14 (m, 2 H, 2-H), 2.18–2.27
(m, 2 H, 1-H), 3.00 (s, 3 H, CH3), 3.56–3.63 (m, 1 H, 3-H), 3.85–
3.91 (m, 1 H, 3-H), 4.03 (dd, J1,11a = 7.72, J1,11a = 1.95 Hz, 1 H,
11a-H), 5.18 (br. s, 1 H, NH), 7.08–7.12 (m, 1 H, 8-H), 7.14 (d, J8,9
166.0 (CO) ppm. IR (KBr, cm–1): ν = 3273 (N–H), 3246, 2945,
˜
2876, 1649 (C=O), 1624, 1593, 1475, 1416, 1377, 1264, 1223 cm–1.
MS (EI, 70 eV): m/z (%) = 291 (100) [M]+, 251 (6), 221 (37), 187
(14), 160 (18), 119 (28), 92 (25), 77 (40), 51 (28). C18H17N3 (275.35):
calcd. C 74.20, H 5.88, N 14.42; found C 74.16, H 5.94, N 14.29.
1,2,3,11a-Tetrahydro-11a-methyl-11-(phenylamino)-5H-pyrrolo-
[2,1-c][1,4]benzodiazepin-5-one (10): Starting materials 7 and aniline
gave 10 as colorless crystals (1.31 g, 4.30 mmol, 86%). m.p. 182–
184 °C) after crystallization from nitromethane. [α]2D0 = +530.5 (c
= 1.0 in CHCl3). 1H NMR (400 MHz, CDCl3): δ = 1.33 (s, 3 H,
CH3), 1.89–2.01 (m, 3 H, 1-H, 2-H), 3.40–3.46 (m, 1 H, 1-H), 3.74–
3.81 (m, 1 H, 3-H), 4.00–4.06 (m, 1 H, 3-H), 6.57 (d, J = 7.9 Hz,
1 H, Ph), 6.60 (br. s, 1 H, NH), 6.89 (d, J = 7.5 Hz, 2 H, Ph), 7.09–
7.14 (m, 2 H, 8-H, 9-H), 7.30–7.34 (m, 1 H, 7-H), 7.48–7.42 (m, 2
H, Ph), 7.96 (dd, J6,7 = 7.83, J6,8 = 1.59 Hz, 1 H, 6-H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 21.9 (C-2), 24.4 (CH3), 39.8 (C-1),
50.4 (C-3), 63.7 (C-11a), 119.3/121.5/123.8/124.2 (Ph), 125.7 (C-
11), 130.5/131.9/132.7/137.4/148.2/156.3 (Ph), 166.0 (CO) ppm. IR
= 8.06 Hz, 1 H, 9-H), 7.40 (ddd, J6,7 = 8.03, J7,8 = 7.12, J7,9
=
1.68 Hz, 1 H, 7-H), 7.96 (dd, J6,7 = 8.03, J6,8 = 1.34 Hz, 1 H, 6-
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 24.2 (C-2), 27.1 (C-1),
29.0 (CH3), 46.9 (C-3), 54.8 (C-11a), 122.6 (Ph), 126.9 (C-11),
127.3/130.4/132.1/147.9/157.6 (Ph), 167.1 (CO) ppm. IR (KBr,
cm–1): ν = 3304 (N–H), 3061, 2887, 1620 (C=O), 1603 (C=N),
˜
1536, 1453, 1406, 1226, 1149 cm–1. MS (EI, 70 ev): m/z (%) = 230
(100) [M + 1]+. C13H15N3O (229.28): calcd. C 68.10, H 6.59, N
18.33; found C 68.22, H 6.67, N 18.45.
(KBr, cm–1): ν = 3376 (N–H), 3218, 3055, 2968, 1651 (C=O), 1616
˜
(C=N), 1597, 1536, 1437, 1354, 1222, 759, 699 cm–1. MS (EI,
70 eV): m/z (%) = 306 (100) [M + 1]+. C19H19N3O (305.38): calcd.
C 74.73, H 6.27, N 13.76; found C 74.35, H 6.19, N 13.71.
Preparation of the 11-Substituted Pyrrolobenzo[1,4]diazepin-5-ones
9–11. General Procedure: HgCl2 (1.75 g, 6.5 mmol) was added at
80–90 °C to a stirred suspension of the monothiolactams 6 or 7
(1.16 g and 1.23 g, 5.0 mmol) and the corresponding amine
(5.0 mL), and the mixture was stirred for a further 30 min at this
temperature. After the system had cooled to room temperature,
chloroform (100 mL) was added and the mixture was filtered
through a plug of Celite. The filtrate was then dried over MgSO4
and filtered, and the solvent and excess amine were evaporated un-
der reduced pressure. The resulting solid was purified by recrystalli-
zation in an appropriate solvent to afford pure colorless crystals in
very good yields.
1,2,3,11a-Tetrahydro-11-(piperidin-1-yl)pyrrolo[2,1-c][1,4]benzodia-
zepin-5-one (11): Starting materials 6 and piperidine afforded a
crude product, which was purified by crystallization from diethyl
ether to give 11 as colorless crystals (1.26 g, 4.45 mmol, 89%). m.p.
105–107 °C. [α]2D0 = 0 (c = 1.0 in CHCl3). 1H NMR (400 MHz,
[D6]DMSO): δ = 1.64 (s, 6 H, 3×CH2), 1.80–1.89 (m, 1 H, 2-H),
1.98–2.07 (m, 1 H, 2-H), 2.22–2.43 (m, 2 H, 1-H), 3.03–3.08 (m, 2
H, CH2), 3.26–3.35 (m, 3 H, CH2, 3-H), 3.83–3.89 (m, 1 H, 3-H),
3.95 (dd, J1,11a = 7.70, J1,11a = 6.24 Hz, 1 H, 11a-H), 7.05 (dd, J8,9
= 8.07, J7,9 = 1.25 Hz, 1 H, 9-H), 7.10–7.14 (m, 1 H, 8-H), 7.45
(ddd, J6,7 = 8.00, J7,8 = 7.19, J7,9 = 1.25 Hz, 1 H, 7-H), 7.76 (dd,
J6,7 = 8.00, J6,8 = 1.47 Hz, 1 H, 6-H) ppm. 13C NMR (100 MHz,
[D6]DMSO): δ = 24.4 (C-2), 24.8 (CH2), 26.1 (C-1), 29.2 (2×CH2),
47.2 (C-3), 50.6 (2×CH2), 56.7 (C-11a), 123.6 (Ph), 126.2 (C-11),
127.0/130.2/132.1/147.2/164.5 (Ph), 166.1 (CO) ppm. IR (KBr,
1,2,3,11a-Tetrahydro-11-(phenylamino)-5H-pyrrolo[2,1-c][1,4]benzo-
diazepin-5-one (9): Starting materials 6 and aniline afforded a crude
product, which was purified by crystallization from propan-2-ol to
yield 9 as colorless crystals (1.32 g, 4.54 mmol, 91%). m.p. 150–
152 °C. [α]2D0 = 0 (c = 1.0 in CHCl3). 1H NMR (400 MHz, CDCl3):
δ = 2.05–2.24 (m, 3 H, 1-H, 2-H), 3.03–3.05 (m, 1 H, 1-H), 3.67–
cm–1): ν = 3141, 2935, 2857, 2833, 1629 (C=O), 1605, 1593, 1452,
˜
1405, 1375, 1240 cm–1. MS (EI, 70 eV): m/z (%) = 283 (100) [M]+.
C17H21N3O (283.37): calcd. C 72.06, H 7.47, N 14.83; found C
72.05, H 7.51, N 14.89.
3.74 (m, 1 H, 3-H), 3.86–3.92 (m, 1 H, 3-H), 4.32 (d, J1,11a
=
7.0 Hz, 1 H, 11a-H), 6.63 (s, 1 H, NH), 6.66 (d, J8,9 = 8.0 Hz, 1 H,
Eur. J. Org. Chem. 2005, 1781–1789
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1787

A. Schmidt, A. Gholipour Shilabin, Jan C. Namyslo, M. Nieger, S. Hemmen
FULL PAPER
1,2,3,10,11,11a-Hexahydro-10-methyl-11-(phenylimino)-5H-pyrrolo-
[2,1-c][1,4]benzodiazepin-5-one (12): Cycloamidine 9 (146 mg,
0.5 mmol) was added portionwise at room temperature under nitro-
gen to a suspension of NaH (60% in mineral oil, 20 mg, 0.5 mmol,
previously washed with n-hexane (2×10 mL)) in anhydrous dime-
thoxyethane (20 mL). A reaction occurred, whereupon the color
changed to yellow. CH3I (0.5 mL) was added to the resulting solu-
tion and the mixture was then stirred for a further 30 min at room
temperature. Evaporation of the solvent and excess CH3I yielded
the N-methylated cycloamidine 12 as a colorless solid (0.15 g,
J10,12 = 1.22 Hz, 1 H, 10-H), 8.08 (dd, J9,10 = 7.98, J9,11 = 1.53 Hz,
1 H, 9-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 19.8 (C-6), 29.2
(C-5), 49.5 (C-7), 62.3 (C-2), 119.3 (C-4b), 124.2/126.2/126.3/126.9/
128.3/128.6 (Ph), 129.3 (C-4a), 129.5/129.7/132.1/132.9/133.1/134.1/
138.9/139.5 (Ph), 165.2 (CO), 166.6 (CO), 166.7(CO) ppm. IR
(KBr, cm–1): ν = 3057, 2967, 1732 (CO), 1709 (CO), 1694 (CO),
˜
1632, 1597, 1495, 1454, 1256 cm–1. MS (EI, 70 eV): m/z (%) = 435
(100) [M]+, 407 (6), 317 (10), 260 (6), 172 (7), 90 (14). C27H21N3O3
(435.48): calcd. C 74.47, H 4.86, N 9.65; found C 74.38, H 4.84, N
9.42.
1
0.49 mmol, 98%). m.p. 65–68 °C. H NMR (400 MHz, CDCl3): δ
Sodium 4,5,6,7-Tetrahydro-3,8-dioxo-2,4-diphenyl-3H,8H-4,7a,12b-
triazadibenzo[e,g]azulen-1-olate (16): NaH (60 % in mineral oil,
20 mg, 0.5 mmol, previously washed with n-hexane (2×10 mL))
was added to a solution of dioxopyrimidine 14 (0.435 g, 1.0 mmol)
in anhydrous dimethoxyethane (20 mL), and the mixture was
stirred at room temperature for a further 30 min. The solvent was
then removed under reduced pressure to afford the product 16 as
a yellow solid (0.444 g, 0.972 mmol, 97%). m.p. Ͼ 250 °C (dec). 1H
NMR (400 MHz, [D6]DMSO): δ = 1.46–1.54 (m, 1 H, 6-H), 1.69–
1.79 (m, 2 H, 5-H, 6-H), 2.10–2.16 (m, 1 H, 5-H), 3.57–3.63 (m, 1
H, 7-H), 3.67–3.77 (m, 1 H, 7-H), 6.76–6.80 (m, 1 H, Ph), 6.91–
6.95 (m, 1 H, Ph), 7.03–7.07 (m, 2 H, Ph), 7.11–7.22 (m, 6 H, Ph),
7.47–7.51 (m, 1 H, 10-H), 7.75 (dd, J9,10 = 7.85, J9,11 = 1.54 Hz, 1
H, 9-H), 7.85–7.87 (m, 2 H, Ph) ppm. 13C NMR (100 MHz [D6]
DMSO): δ = 20.6 (C-6), 28.3 (C-5), 48.8 (C-7), 87.9 (C-2), 121.6
(Ph), 122.4 (C-4b), 123.6/124.7/125.8/126.4 (Ph), 126.5 (C-4a),
126.8/128.7/130.2/130.5/131.7/132.9/141.7/143.9/147.2 (Ph), 164.7
= 1.88–1.96 (m, 2 H, 2-H), 2.10–2.20 (m, 1 H, 1-H), 2.77–2.83 (m,
1 H, 1-H), 2.93 (s, 3 H, CH3), 3.60–3.67 (m, 1 H, 3-H), 3.80–3.85
(m, 1 H, 3-H), 4.28 (d, J1,11a = 6.72 Hz, 1 H, 11a-H), 6.82 (d, J =
7.58 Hz, 2 H, Ph), 6.95 (t, J = 7.27 Hz, 1 H, 8-H), 7.13 (d, J8,9
=
8.19 Hz, 1 H, 9-H), 7.23–7.27 (m, 4 H, Ph), 7.48 (t, J = 7.82 Hz, 1
H, 7-H), 7.86 (d, J6,7 = 7.82 Hz, 1 H, 6-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 24.0 (C-2), 28.3 (C-1), 42.4 (CH3), 46.9 (C-
3), 60.2 (C-11a), 120.8/122.0/123.5/125.7/129.0/130.0 (Ph) 131.5 (C-
11), 132.4/144.4/149.9/153.3 (Ph), 166.5 (CO) ppm. IR (KBr, cm–1):
ν = 3347, 2968, 2875, 1637 (C=O), 1591, 1457, 1412, 1359 cm–1.
˜
MS (EI, 70 eV): m/z (%) = 306 (100) [M + 1]+. C19H19N3O
(305.38): calcd. C 74.73, H 6.27, N 13.76; found C 74.43, H 6.21,
N 13.56.
Preparation of the 3H-2,4-Dioxopyrimidines 13, 14. General Pro-
cedure: A mixture of the cycloamidines 8 or 9 (1.145 g and 1.455 g,
respectively, 5.0 mmol) and bis(2,4,6-trichlorophenyl) phenylma-
lonate (5.0 mmol) was heated at 170–180 °C for 10 min in a Zincke
apparatus under high vacuum. The residue was treated with diethyl
ether (20 mL) to give a precipitate, which was collected by filtration
and washed with diethyl ether. The crude solids were purified by
crystallization in an appropriate solvent.
(CO), 166.4 (2CO) ppm. IR (KBr, cm–1): ν = 3057, 2934, 1634
˜
(C=O), 1575, 1550, 1488, 1404, 1068 cm–1. MS (EI, 70 eV): m/z
(%) = 435 (4) [M]+, 390 (12), 185 (100), 119 (9), 93 (34), 66 (13).
C27H20N3NaO3 (457.47): calcd. C 70.89, H 4.41, N 9.19; found C
70.53, H 4.68, N 9.36.
4,5,6,7-Tetrahydro-4-methyl-2-phenyl-4,7a,12b-triazadibenzo[e,g]azu-
lene-1,3,8-trione (13): Starting materials cycloamidine 8 and
bis(2,4,6-trichlorophenyl) phenylmalonate (2.695 g, 5.0 mmol)
yielded a crude product, which was purified by crystallization from
propan-2-ol to give 13 as pale yellow crystals (1.417 g, 3.80 mmol,
76%). m.p. 225–227 °C. 1H NMR (400 MHz, CDCl3): δ = 0.94–
1.07 (m, 1 H, 6-H), 1.67–1.85 (m, 1 H, 6-H), 2.04–2.10 (m, 1 H, 5-
H), 2.35–2.44 (m, 1 H, 5-H), 3.20 (s, 3 H, NCH3), 3.54–3.60 (m, 1
H, 7-H), 3.69–3.75 (m, 1 H, 7-H), 4.82 (s, 1 H, 2-H), 7.27–7.33 (m,
5 H, Ph), 7.38–7.45 (m, 2 H, 11-H, 12-H), 7.62 (ddd, J9,10 = 8.04,
J10,11 = 7.27, J9,12 = 1.65 Hz, 1 H, 10-H), 8.03 (dd, J9,10 = 8.04,
J9,11 = 1.34, 1 H, 9-H) ppm. 13C NMR (100 MHz, CDCl3): δ =
20.3 (C-6), 29.3 (C-5), 35.6 (CH3), 49.3 (C-7), 61.5 (C-2), 120.6 (C-
4b), 126.0/126.4/128.1/128.5 (Ph), 129.0 (C-4a), 129.3/131.0/132.2/
132.7/133.8/140.1 (Ph), 165.3 (CO), 166.7 (CO), 168.4 (CO). IR
4,5,6,7-Tetrahydro-2-methyl-2,4-diphenyl-4,7a,12b-triazadibenzo[e,g]-
azulene-1,3,8-trione (17): A suspension of pyrimidine-olate 16
(0.457 g, 1.0 mmol) in anhydrous dimethoxyethane (20 mL) was
treated with CH3I (1.0 mL) at room temperature and the mixture
was then heated at 60 °C for 3 h. Evaporation of the solvent and
excess CH3I under reduced pressure gave a residue, which was puri-
fied by flash column chromatography on silica gel (ethyl acetate/
petroleum ether, 2:1) to afford the dioxopyrimidine 17 as a colorless
solid (0.40 g, 0.89 mmol, 89 %). m.p. 112–114 °C. 1H NMR
(400 MHz, [D6]DMSO): δ = 0.58–0.66 (m, 1 H, 6-H), 0.79–0.89
(m, 1 H, 6-H), 1.49–1.62 (m, 2 H, 5-H), 1.56 (s, 3 H, CH3), 3.06–
3.12 (m, 1 H, 7-H), 3.48–3.55 (m, 1 H, 7-H), 7.16–7.22 (m, 3 H,
Ph), 7.26–7.29 (m, 2 H, Ph), 7.35–7.44 (m, 5 H, Ph), 7.52 (ddd,
J11,12 = 7.98, J10,11 = 7.09, J9,11 = 1.32 Hz, 1 H, 11-H), 7.70 (dd,
J11,12 = 7.98, J10,12 = 1.07 Hz, 1 H, 12-H), 7.73–7.77 (m, 1 H, 10-
H), 7.89 (dd, J9,10 = 7.92, J9,11 = 1.32 Hz, 1 H, 9-H) ppm. 13C
NMR (100 MHz [D6]DMSO): δ = 19.6 (C-6), 23.4 (CH3), 28.9 (C-
5), 49.6 (C-7), 61.5 (C-2), 118.8 (C-4b), 125.1/125.2/127.0/127.4/
128.5/128.6 (Ph), 129.6 (C-4a), 129.9/130.0/132.4/132.8/134.3/139.6/
140.0/140.7 (Ph), 164.8 (CO), 168.9 (CO), 169.0 (CO) ppm. IR
(KBr, cm–1): ν = 3082, 2972, 1724 (C=O), 1697 (C=O), 1682
˜
(C=O), 1632, 1493, 1452, 1380, 1354, 1258, 1155 cm–1. MS (EI,
70 eV): m/z (%) = 373 (100) [M]+, 344 (27), 305 (7), 256 (8), 187
(22), 118 (18), 89 (17), 63 (12). C22H19N3O3 (373.41): calcd. C
70.76, H 5.1, N 11.25; found C 70.51, H 5.22, N 10.96.
(KBr, cm–1): ν = 3069, 2989, 1720 (C=O), 1685 (C=O), 1640
4,5,6,7-Tetrahydro-2,4-diphenyl-4,7a,12b-triazadibenzo[e,g]azulene-
1,3,8-trione (14): The starting materials cycloamidine 9 and
bis(2,4,6-trichlorophenyl) phenylmalonate (2.695 g, 5.0 mmol) gave
14 as pale yellow crystals after recrystallization from butan-2-ol
(1.78 g, 4.09 mmol, 82%). m.p. 207–208 °C. 1H NMR (400 MHz,
CDCl3): δ = 0.90–0.98 (m, 1 H, 6-H), 1.56–1.65 (m, 2 H, 5-H, 6-
H), 1.73–1.80 (m, 1 H, 5-H), 3.41–3.47 (m, 1 H, 7-H), 3.67–3.74
˜
(C=O), 1598, 1490, 1454, 1356, 1259 cm–1. MS (EI, 70 eV): m/z (%)
= 450 (100) [M + 1]+, 289 (6), 261 (8), 172 (16), 132 (20), 104 (15),
77 (14). C28H23N3O3 (449.51): calcd. C 74.82, H 5.16, N 9.35;
found C 74.58, H 5.18, N 9.08.
Supporting Information: VT 1H NMR spectra, and HSQC and
(m, 1 H, 7-H), 4.94 (s, 1 H, 2-H), 7.13–7.20 (m, 3 H, Ph), 7.28– HMBC NMR correlations of 9, and 1H NMR and 13C NMR spec-
7.43 (m, 7 H, Ph), 7.47–7.51 (m, 1 H, 11-H), 7.53 (dd, J11,12 = 8.07,
tra in CDCl3 and [D6]DMSO as well as the HMBC spectra of 14
J10,12 = 1.22 Hz, 1 H, 12-H), 7.70 (ddd, J9,10 = 7.98, J10,11 = 7.34, are presented in the Supporting Information.
1788
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 1781–1789

A New Ring System Related to Aspergillus Alkaloids
FULL PAPER
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DNA Interactions (Eds.: S. Neidle, M. J. Waring), Macmillan
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[24] A. Schmidt, T. Mordhorst, M. Nieger, Nat. Prod. Res., in press.
[25] A. Schmidt, T. Mordhorst, ARKIVOC 2003, XIV, 233.
[26] A. Schmidt, T. Habeck, M. K. Kindermann, M. Nieger, J. Org.
Chem. 2003, 68, 5977.
Acknowledgments
We thank Prof. E. Breitmaier (Bonn) and Prof. P. Böchl (Clausthal)
for helpful discussions. Prof. F. Vögtle, Prof. K.-H. Dötz, and Prof.
E. Niecke (Bonn) are gratefully acknowledged for providing the
X-ray facilities. We thank the Deutsche Forschungsgemeinschaft
(DFG) for the financial support.
[27] A. Schmidt, A. Gholipour Shilabin, M. Nieger, Heterocycles
2004, in press.
[28] A. Schmidt, N. Kobakhidze, Heterocycles 2002, 57, 2231.
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Received: October 16, 2004
Eur. J. Org. Chem. 2005, 1781–1789
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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